Liquid vitamin preparation



atent 2,850,429 Patented Sept. 2, 1958 dice .lohn .l. Gulesich andGeorge M. Pierso], Jr., Philadelphia, Pa, assignors to Smith, Kline &French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania NoDrawing. Continuation of application Serial No. 522,388, .luly 15, 1955.This application November 18, 1957, Serial No. 696,934

13 Claims. (Cl. 16781) This invention relates to a liquid vitaminpreparation which is useful for the treatment of anemia andmalnutritional states.

Unexpectedly, the use of the preparation in accordance With thisinvention provides a surprisingly high level of absorption or" cobalaminvitamins. It has been found that the preparation of this inventionproduces serum levels of cobalamin vitamins which are greatly in excessof the serum levels which can be achieved with heretofore knownpreparations. This is of great importance, for example, in the treatmentof geriatic patients since they normally absorb very little of thecobalamin vitamins. In clinical tests there were achieved markedlyhigher cobalamin vitamin serum levels with the preparation of thisinvention than Were achieved utilizing the combination or" a cobalaminvitamin and intrinsic factor.

The liquid vitamin preparation in accordance with this invention has asits essential ingredients a cobalamin vitamin, ethyl alcohol and water.The preferred cobalamin vitamin is vitamin B cyanocobalamin. Exemplaryof other satisfactory cobalamin vitamins are the compounds where anon-toxic radical such as a hydroxy, nitro or chloro radical replacesthe cyano radical in cyanocobalamin, for example, hydroxycobalamin (Banhydrous hydroxycobalamin (B nitrocobalamin (E chlorocobalamin. Furtherexemplary of satisfactory cobalamin vitamins, are cobalamin,dicyanocobalamin, thiocyantocobalamin, sulfatocobalamin,sulfitocobalamin and the hydrogen sulfide addition product ofcyanocobalamin.

The cobalamin vitamin will be present in an amount from about 25 toabout 1500 micrograms percent, that is, from about 25 to about 1500micrograms per 100 ml. of the final preparation. Preferably thecobalamin vitamin will be present in the preparation in an amount offrom about 50 to about 500 micrograms percent, that is, from about 50 toabout 500 micrograms per 100 ml. of the final preparation. The volume ofthe ethyl alcohol present will be from about to about 40% of the totalvolume of the preparation and preferably from about to about of thetotal volume of the preparation. Water is employed in an amount to bringthe preparation to the volume of 100%.

Advantageous results are achieved if inositol or a polyhydric alcohol ofthe formula C H O such as, for example, sorbitol or mannitol is alsoemployed. When used the inositol will be present in an amount by weightof from about 1% to about 15 of the total volume of the preparation, theweight being measured in grams and the volume being measured in cubiccentimeters (W./v.). The polyhydric alcohol when used will be present inan amount by weight of from about 10% of the volume of the finalpreparation (the weight being measured in grams and the volume beingmeasured in cubic centimeters) and up to the limit of solubility in thepreparation. For superior results it is preferred to have both thepolyhydric alcohol and the inositol present in the preparation.

Advantageous results are also achieved if cafieine or a caffeine salt isadded to the preparation containing the cobalamin vitamin and ethylalcohol or additionally containing inositol and/or the polyhydricalcohol. Exemplary of satisfactory caffeine salts are calfeine citrate,cafleine phosphate, caffeine sulfate and cafieine hydrochloride.Citrated cafieine may be substituted for catfeine citrate. It isintended that the term cafieine as used in the description and claimscovers both caffeine and pharmaceutically suitable forms of caffeinesuch as a caffeine salt. When employed, the cafieine will be present inthe preparation in an amount by weight equal to from about 0.1% of thevolume of the preparation and up to the limit of solubility in thepreparation but not exceeding an amount by weight equal to 3% of thevolume of the preparation, the weights being measured in grams and thevolume being measured in cubic centimeters (W./v.).

Most advantageous results are achieved if all of the above mentionedingredients, namely, a cobalamin vitamin, ethyl alcohol, inositol, apolyhydric alcohol and calfeine are present in the preparation of thisinvention together with water to bring the volume up to Otherpharmaceutical agents may be added, if desired, such as, for example, alipotropic agent such as betaine, choline or methiomine or other Bvitamins such as riboflavin, pyridoxine hydrochloride or nicotinamide.

Where ingredients in addition to the cobalamin vitamin and ethyl alcoholare added to the preparation, water is still added in an amount to bringthe volume of the preparation to 100%.

If desired, other agents such as, for example, a ferric ion producingsalt may be added. Thus, for example, ferric ammonium citrate or solubleferric pyrophosphate may be employed in an amount by weight of fromabout 0.1% to about 1% of the volume of the preparation, the weightbeing measured in grams and the volume being measured in cubiccentimeters (w./v.).

The preparation in accordance with this invention is readily preparedusing simple techniques well known to the art. Thus, for example, it maybe prepared by first placing about 50% of the volume of water requiredin a vessel and then adding the remaining ingredients in any order whilestirring. Sufiicient water to bring the volume up to 100% may then beadded and the preparation stirred.

This invention will be further clarified by reference to the followingspecific examples:

Example 1 Vitamin B micrograms 167 Ethyl alcohol, U. S. P cc 16 Water q.s. to make volume of preparation 100 cc.

Example 2 Vitamin B micrograms 1,000 Ethyl alcohol, U. S. P cc 30 Waterq. s. to make volume of preparation 100 cc.

Example 3 Vitamin B micrograms 200 Ethyl alcohol, U. S. P cc 20 inositolgm Water q. s. to make volume of preparation 100 cc.

Example 4 Vitamin B micrograms 200 Ethyl alcohol, U. S. P cc 20 Sorbitolg 50 Water q. s. to make volume of preparation 100 cc.

Water q. s. to make volume of preparation 100' cc.

Example Sulfitocobalamin micrograms 167 Ethyl alcohoLa cc 16 Inositol gm3 Sorbitol gm 28 Citrated cafieinec a gm 1.296

Water q. 540mm volume of preparation cc.

This: application is a continuing application based on applicationSerial No. 522,388, filed July 15, 1955, now abandoned. w

What is claimed is: j p

1. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10% to" about 40%W./v. of ethyl alcohol, from about 10% W./v. up to the limit ofsolubility of apolyhydric alcohol having the formula C H 'O and water. 7i

2. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10% to about 40%w./v. of ethyl alco-' hol, from about 1% to about 15% w./v. ofino-sitol, from about 10% w./v. up to the" limit of solubility of apolyhydric alcohol having the formula C H O and water.

3. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10% to about 40%w./v..oi ethyl alcohol, from about 10% w./v. up to the limit ofsolubility of a polyhydric alcohol having the formula C H O from about0.1% w./v. up to the limit of solubility but not in excess of 3% w./v.of caffeine and water. V

4. A liquid vitamin preparation comprising from: about- 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10% to about 40%W./v. of ethyl alcohol, from about 1% to about 15% w./v. of inositol;from about 10% w./v. up to the limit of solubility of a polyhydricalcohol having the formula C H O fromabout 0.1% w./v. up tothe limit ofsolubility but notin excess of 3% w./v. of cafieine and water. 7 5. Aliquid vitamin preparation comprising from about- 25 to about 1500micrograms percent of cyanocobalamin, from about 10% to about 40% w./v.of ethyl alcohol, from about 10% W./V. up to the limit of solubility ofa polyhydric alcohol having the formula C H O and water. r 6. A liquidvitamin preparation comprising from about; 25 to about 1500 microgramspercent of cyanocobalamin, from about 10% to about 40% w./v. of ethylalcohol,- from about 1% to about 15% w./v. of inositol,;from' about 10%'w./v. up to the limit of solubility of a poly-. hydric alcohol havingthe formula C H O andwaten; 7. A liquid vitamin preparation comprisingfrom'about 25 to about 1500 micrograms percent of cyanocobalaminvitamin, from about 10% to about 40% W./V. of ethyl/ alcohol, from about10% w. /v. up to the limit of solubility of a polyhydric alcohol havingthe formula C l-1 0 from about 0.1% w./v. up to the limit of solubilitybut not in excess of 3% w./v. of caffeine and water; a

8. A liquid vitamin preparation comprising from about" 25 to about 1500micrograms percent of cyanocobalamin, from about 10% to about 40% w./ v.of ethyl alcohol, from about 1% to about 15% w./v. of inositol,fromabout 10% w./v. up tothe-limit of solubilityof'a polyhydric alcoholhaving the formula C H -O from about 0.1% w./v. up to the limit ofsolubility but not in excessof 3% W./v. of cafieine and water; p

9. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10% to about 40%w./v. of ethyl alcohol, from about 10% w./v. up to the limit of solubility of sorbitol and water.

10. A liquid vitamin preparation comprising fromabout Example 5 7Vitamin B micrograrns 167 Ethyl alcohol cc 16 Inositol gm; 3 Sorbitolgr'n 28* Water q. s. to make volume of preparation 100 cc. Example 6 V 7Vitamin B "micrograms" 167 Ethyl alcohol cc 16 Inositol gm 3 Sorbitol gm28 Citrated' caffeine gm 1.296 Water q. s. to make volume of preparation100 cc.

I Example 7 Vitamin B micrograms 500 Ethyl alcohol cc 25 Cafieinephosphate gm 0.5

Water q. s. to make volume of preparation 100 cc.

Example 8 Vitamin B micrograms 167 Ethyl alcohol; cc 16 Inositol -2 gm 3Sorbitol gm. 28 Citrated cafieineue gm 1.296 Riboflavin gm 0.012 VitaminB gm 0.04 Nicotinamide gm 0.14 Choline dihydrogen citrate gm 3.0 Betainegm 14.0 Soluble ferric pyrophosphate gm 0.70 Water q. s. to make volumeof preparation 100 cc.

Example 9 Hydroxycobalamin micrograms 167 Ethyl alcohol cc 16 Water q.s. to make volume of preparation 100 cc.

Example 10 Nitrocobalamin micrograms 167 Ethyl alcohol cc 16 Water q. s.to make volume of preparation 100 cc.

Example 11 Chlorocobalamin micrograms 200 Ethyl alcohol cc 20 Sorbitolgm 50 Water q. s. to make volume of preparation 100 cc.

Example-l2 Dicyahocobalamin micrograms 167 Ethyl alcohol cc 16 Inositolgm 3 Sorbitol gm 28 Water q. s; to make volume .of preparation 100 cc.

Example Thiocyanotocobalamin micrograms 167 Ethyl alcohol cc 16 Inositolg gm 3 Sorbitol 9. L g m 28 Water q. s. to make volume of preparation100cc.

Example 14 Sulfatocobalamin micrograms 167 Ethyl alcohol cc l6 Inositolgm 3 Sorbitol 'gm 28 V Citrated cafieine gm 11296 2510 about 1500micrograms-percent of cyanocobalamin, fIom about 10%" to about40% w./v.of "ethyl alcohol,

from about 10% w./v. up to the limit of solubility of sorbitol andwater.

11. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10% w./v. up tothe limit of solubility of a polyhydric alcohol having the formula C H Oand an aqueous vehicle.

12. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of a cobalamin vitamin, from about 10 0 w./v. up tothe limit of solu- 10 bility of sorbitol and an aqueous vehicle.

13. A liquid vitamin preparation comprising from about 25 to about 1500micrograms percent of cyanocobalamin, from about 10% w./v. up to thelimit of solubility of sorbitol and an aqueous vehicle.

References Cited in the file of this patent Modern Drugs, January 1952,pp. 24-26.

J. of the Am. Pharm. Assoc., Pract. Pharm. Ed., vol. 13, No. 1, January1952, p. 34.

Drug and Cosmetic Ind., vol. 12, No. 3, March 1953, pp. 320-321.

Unlisted Drugs, vol. 14, No. 8, Aug. 31, 1952, p. 115.

1. A LIQUID VITAMIN PREPARATION COMPRISING FROM ABOUT 25 TO ABOUT 1500MICROGRAMS PERCENT OF A COBALAMIN VITAMIN, FROM ABOUT 10% TO ABOUT 40%W./V. OF ETHYL ALCOHOL, FROM ABOUT 10% W./V. UP TO THE LIMIT OFSOLUBILITY OF A POLYHYDRIC ALCOHOL HAVING THE FORMULA C6H14O6 AND WATER.